L0301P81 - Acute and Chronic Inflammation
__TOC__ Inflammation *primary function is to eliminate a pathogenic insult and remove injured tissue components in order to restore homeostasis *can also occur in the absence of pathogens *depending on the trigger the inflammatory response has a different physiological purpose and consequences Terminology *inflamed tissues are named accordingly: **prefix = tissue name (in Latin or Greek) **plus suffix = itis ***e.g. tonsillitis, appendicitis, hepatitis *exceptions: pneumonia; pleurisy Acute Inflammation (AI) *rapid onset and short-lasting *symptoms may only be present for a few days but may persist for a few weeks *represents a series of reactions involving blood vessels and connective tissue cells *recognised by 5 cardinal signs: **calor - heat **rubor - redness **dolor - pain **tumor - swelling **functio laesa - loss of function Inflammatory Molecules *complement C3a and C5a *chemokines (attract inflammatory cells) **Interleukin-8 (IL-8/CCL8) ***produced by macrophages, epithelial and some endothelial cells *monocyte chemoattractant protein 1 (MCP1/CCL2) **induced by platelet derived GF **produced by monocytes, macrophages, dendritic cells *cytokines **IL-1 ***produced by monocytes, macrophages, dendritic cells, fibroblasts and others **tumour necrosis factor α (TNFα) ***produced by monocytes **IL-6 ***produced by T cells and macrophages Process of AI *a series of reactions involving blood vessels and connective tissues cells #transient vasoconstriction of arterioles ##blanching of the skin - not always seen #sustained vasodilation of arterioles and venules, and hyperaemia ##increased blood flow = redness, heat #increased vascular permeability ##increased leakiness of vessels to fluid and protein ##formation of inflammatory exudate/oedema ##swelling, pain, loss of function #stasis ##blood flow slows or stops (very rarely) due to constriction #margination and diapedesis ##escape of leukocytes from circulation to tissue ###adherence of neutrophils/monocytes to the vessel wall ###movement through close inter-endothelial junctions and digestion of the basement membrane to enter the extravascular space #chemotaxis ##movement of leukocytes to site of injury due to chemical attraction ##pain, loss of function #phagocytosis ##ingestion of necrotic debris and toxins Formation of Tissue Fluids *physical forces: **act across capillary walls (Starling forces) **cause fluid to move from within vessels to extravascular space, and vice versa **determine how much fluid is lost to extravascular space Types of Tissue Fluids Transudate *forms in normal tissue *slow seepage of fluid through closed endothelial cell junctions and proteins via momentary opening of cell junctions *lymphatics return fluid to circulation Exudate *more opening of inflamed vessel cell junctions allowing increased seepage *contains increased protein concentration (e.g. fibrinogen) compared to transudate but still less compared to normal plasma Mediators of AI & Exudate Formation Following injury: *mast cells, basophils and platelets release histamine which stimulates: **opening of inter-endothelial cell junctions (via actin/ myosin contraction) **vasodilatation *histamine release is illustrated by: **pallor - vasoconstriction **flare (redness) - vasodilatation **weal (swelling) – exudate *other mediators such as complement components, arachidonic acid metabolites, kinins, other amines also involved Exudation Formation Rate *depends on severity of injury Types of Leakage Response *histamine type **mild injury, minimal damage **brief by intense response as junctions open and then rapidly close *biphasic type **moderate tissue damage **histamine response followed by a prolonged, intense, delayed phase **due to eventual death of some endothelial cells as result of initial injury *prolonged type **due to severe injury **direct vascular damage **therefore immediate, intense and prolonged response Composition of Exudate *depends on nature of injury Types *serous inflammatory exudate **low protein levels and very little leukocytic (WBC) emigration **e.g. skin blister *fibrinous exudate **high protein levels **e.g. fibrinous pericarditis or pleurisy ***fibrinogen (soluble in circulation) polymerises in the presence of protease thrombin to produce fibrin (insoluble & sticky in tissue) *suppurative exudate **much leukocytic emigration due to infection (infection & leukocytes form pus) **high levels of neutrophils **e.g. meningitis *hemorrhagic exudate **injury directly damages vessels and many blood components (fluid, proteins, RBC, WBC, etc.) leak out **eg. bleeding peptic ulcer Factors Controlling Exudate Cessation *endogenous mediators will wear off *arterioles gradually constrict *platelets “plug up” leaking vessel *distensibility of the tissue is limited **only so far the tissue can stretch *increased lymphatic drainage Cellular Aspects of Acute Inflammation *leukocytes found in extravascular spaces comprise the infiltrate *characteristic cell of AI = neutrophil **phagocytic cell with multi-lobed nucleus **contains endogenous pyrogens, chemotactic factors & vasodilators *as AI progresses, monocyte/macrophages enters the tissue via margination and diapedesis **a mononuclear phagocytic cell **clears debris and has function in immune response under certain circumstances **can promote chronic inflammation Neutrophils and NETosis *in the presence of pathogens can undergo NETosis (neutrophil extracellular traps) *involves the release of a chromatin net that can trap and destroy pathogens Summary of consequences of AI 1. Exudate Formation *fluid - water, electrolytes; dilutes toxins *proteins **antibodies important in immunity **fibrin forms; acts as “tissue glue” **complement helps phagocytosis 2. Infiltrate Formation *neutrophils - phagocytosis, release inflammatory mediators, NETosis *macrophages - phagocytosis and immune function, release inflammatory mediators Activation of Acute Inflammation *activation of IL-1β requires two signals **activation of NF-κB ***a family of prototypic inflammatory transcription factors ***regulate the expression of hundreds of genes associated with components of the inflammasome, cell cycle and cellular viability **activation of caspase 1 ***cleaves pro IL-1β to IL-1β Inflammasomes *TLR receptor binding to PAMP or DAMP *signals release of NF-κB *results in production of cytokines in their pro-form (inactive) *cytokines activated by caspase-1 *caspase-1 is originally in its inactive form as part of the inflammasome *when the inflammasome is activated by various signals, caspase-1 is released Sequelae of Acute Inflammation *sequela is any possible result, complication or conclusion of a pathological process Resolution *complete restoration of normal structure and function of tissue *e.g. mild thermal burn, lobar pneumonia Suppuration *excessive exudate or pus *contains both viable and non-viable neutrophils and pyogenic bacteria *can lead to abscess and scar Repair and Healing  Necrotic tissue is removed and replaced by: *regeneration **division of surviving parenchymal cells **e.g. liver, bone, kidney, but not brain *organisation **usual outcome **rapid replacement of specialised cells by a collagen scar (fibrosis) or glial scar in brain (gliosis) *often a combination of regeneration and organisation may occur **e.g. skin wound - epidermis regenerates while dermis undergoes organisation Chronic Inflammation *injury persists leading to constant inflammation and constant attempts at healing *immune system cells are recruited *lymphocytes found in tissue and scarring usually occurs Chronic Inflammation (CI) *different process from AI clinically **long-lasting (weeks/months/years) **involves immune mechanisms *can occur following acute inflammation **irritant stimulus persists, AI cannot cope, immune response initiated **e.g. chronic abscess *can occur as a primary response to certain stimuli **due to special nature of the irritant, immune response initiated **e.g. tuberculosis Characteristics of CI *productive rather than exudative **infiltrate forms immediately *pleomorphic cellular reaction **many different cell types present *destruction and healing occur concurrently   Forms of Chronic Inflammation Chronic Fibrous Inflammation *deposition of collagen scar is prominent *may lead to: **stricture ***abnormal narrowing of a passage ***e.g. chronic duodenal ulcer **stenosis ***narrowing of an opening ***e.g. rheumatic heart disease **ankylosis ***fusion of joints causing immobility ***e.g. rheumatoid arthritis Chronic Serous Inflammation *occurs in serous membranes: pericardium, pleura, peritoneum, synovial membrane *serous fluid is produced by these membranes normally, however when it is chronically inflamed the membranes produce more serous fluid Chronic Suppurative Inflammation *occurs following AI *pus is formed in great quantities *immune response and phagocytosis evident Chronic Ulcerative Inflammation *occurs when a deep excavation (ulcer) forms in tissue *often caused by specialised bacterium *e.g. **tropical ulcer - Mycobacterium ulcers **chronic peptic ulcer - Helicobacter pylori Chronic Granulomatous Inflammation *occurs as a primary response to stimuli *characterised by a solid tissue nodule - granuloma (“grain-like lump”) **due to destruction of tissue by specialised microbes and/or autoimmunity *e.g. **leprosy - Mycobacterium leprae **tuberculosis - Mycobacterium tuberculosis Active Chronic Inflammation *occurs after a long course of CI with intermittent episodes of AI *symptoms are worst during acute episodes when tissue damage is maximal *e.g. rheumatoid arthritis - autoimmunity Cellular Aspects of Chronic Inflammation Pleomorphic Response *many different cell types present in tissue at the same time *all cells are derived from white blood cells **granulocytes ***neutrophils ***eosinophils ***basophils (form mast cells in tissue) **mononuclear cells ***monocyte/macrophage ***lymphocytes infiltrate the tissue ****T cells - cellular immunity ****B cells - humoral immunity Cellular Aspects of Granulomatous CI *typical cell-mediated response *microscopic appearance of a granuloma: **centre of necrosis **many T-lymphocytes and macrophages **multinucleated giant cells **epithelioid histiocytes (activated macrophage) **fibroblasts laying down collagen at periphery - leads to major scarring Summary - Chronic Inflammation *a prolonged response to persistent injury *can occur either as sequela of acute inflammation or ab initio *productive, pleomorphic response in which the immune system is activated *damage to tissue and attempts at healing are progressing at the same time